1. Field of the Invention
Embodiments of the present invention relates to designs, syntheses and uses of templated chemical routes for synthesizing interlocked macromolecular structures and orderly or programmed entanglements that are referred sometimes herein as “knotty polymers”.
More specifically, embodiments of this invention makes uses of combined supramolecularly assembled macroinitiator or iniferters and living or living-radical polymerization or polyhomologation in a ring expansion mechanism for synthesizing interlocked macromolecular structures and orderly entanglements that are referred sometimes herein as knotty polymers. This also includes the living polymerization from a supramolecularly assembled macroinitiator followed by ring or loop formation by end-group coupling.
2. Description of the Related Art
Supramolecular assembly and the study of orderly molecular entanglements offer unique challenges in the most subtle and demanding aspects of stereochemistry, regiochemistry, and mechanistic control. Geometry, symmetry, and topology unite in chemical templates to enable reaction pathways leading to intricate extended macromolecular architectures. By combining in-situ living or living free-radical polymerization methods with supramolecularly ordered templates, new paradigms in macromolecular structure-property relationships are expected as inspired by Knot Theory.
2.1 Knot Theory
Mathematical Knot Theory, the formal discipline dealing with knots and links, evolved from the early work of chemists in the middle of the 19th century. Mathematicians describe a “knot” as a cord that is intertwined with itself, with its loose ends joined so that it cannot become untangled. This definition makes a macrocycle, a rudimentary knot, or the “unknot”. If two or more knots are interlocked with each other, the result is called a “link”. A [2]-catenane is a link composed of two unknots. Since their inception, chemical templates and supramolecular assembly have provided exciting new molecular topologies that are inspired by Knot Theory. However, both art and science have examples of intractable and symbolic knots, which include the Borromean sign, the Book of Kells, the works of Escher, Möbius strip, etc. as illustrated in FIG. 1. Topology in association with Graph Theory is a branch of mathematics of high interest. Chemical topology is Graph theory applied to chemistry. Many aspects of chemical topology from DNA to stereochemical reactions have been studied. This realm of orderly molecular entanglements encompasses a melange of well-reported interlocked molecular and supramolecular architectures as espoused by Sauvage, Stoddart, Wasserman, Busch, Walba, etc.: from nano-objects to macrame and molecular braids almost analogous to weaving, knitting, and crocheting and their three-dimensional counterparts. A number of reports have demonstrated intricate sequences of steps (threadings, cross-overs, ring closings, and other linkages) in order to form complicated orderly knot entanglements with elements of chirality.
There are many structural motifs that have been achieved through small molecule templates, however very few if none have been demonstrated with high molecular weight (MW) polymers except through statistical tethering of telechelics. The present invention offers a novel synthetic route to produce model high MW entangled polymers by programmed sequential steps from self-assembly to living polymerization. The resulting molecules are referred to herein as “knotty polymers”.
2.2 Molecular and Supramolecular Assembly
A chemical template organizes an assembly of molecules, with respect to one or more geometric loci, in order to achieve a particular link. A particular assembly focuses on those that generate interlocked assemblies between otherwise independent molecules; e.g., rotaxanes, catenanes, separate knots, knots joining strands, mechanically linked oligomers and polymers, and braided, knitted or woven structures constructed by the interlocking of linear molecules. Creating continuous and intricate molecular architectures requires a particular linking of molecules to establish an interlocking architecture. This requires the formation of one or more chemical bonds, while the template organizes the assembly of atoms. Equally important, the template may involve components that, like catalysts, do not become permanent parts of the molecular architectures and may be used for disassembly. There are two classes of chemical templates: kinetic templates that influence the mechanistic pathway and thermodynamic or equilibrium templates that select and bind certain complementary structures from among an equilibrating mixture of structures. Kinetic templates are of primary importance in generating molecularly interlocked structures. Supramolecular structures involve multiple levels of interactions and are considered larger in size than a typical complex, but basically use the same assembly elements.
2.1.1 Chemical Template Design
In any chemical template, an anchor constitutes the first component (a metal ion, ion pair complement, partial charge complement, or hydrogen bonded partner); this anchor holds an appropriate conjugate component, or components. One important role performed by such an anchor-constrained component is to build a turn into the emerging structure; appropriately, such a component is called a molecular turn. Molecular turns have two or more terminal, or near terminal, reactive groups, each pointed in a critical, often in the same direction. This simple kind of molecular template is composed of an anchor and a molecular turn, and the turn may be intrinsic in the structure of the conjugate component or, in the case of a more flexible conjugate component, it may be caused by the anchor.
A typical design uses Sauvage's highly successful phenanthroline templates as illustrated in FIG. 2, as well as alternative metal ion templates that are currently under investigation by a number of groups. Hydrogen bonding anchors for templates are almost as diverse as are metal ion anchors, but they differ sharply in that they generally involve multicentric interactions. DNA is an example that is also of high interest biologicially. There are many other examples which include Busch:Stoddart secondary ammonium ion anchors and the Hunter:Vogtle:Leigh diamide templates. Cyclodextrin templates contain significant hydrogen bonds. The Stoddart template is formed between electron rich aromatic ether moieties and paraquat-containing moieties, as p-donor: acceptor templates as illustrated in FIG. 3. In summary, these important templates include, but are not limited to, ion-ligand complexation, p-p stacking, ion-dipole attractions and hydrogen bonding interactions, which combine to force molecular strands into turns.
2.1.2 Kinetic Template Effect
The kinetic template effect is the ability of the metal ion anchor to predictably control the spatial orientation of reactive groups during the formation of critical linkages. Metal ion anchors offer the advantage that they can often be readily removed, leaving the interlocked structure intact even after the cyclization reaction Innumerable examples have been reported of macrocycles, macrobicycles, macrocycles with appendages, appended macrocycles, ditopic, tritopic, etc.
Statistical vs. Preformed
An important aspect of chemical template synthesis is in understanding statistical threading—an appropriate baseline methodology since it depends on the probability that a linear molecule will penetrate and occupy the space within a macrocycle without the benefit of any particular intermolecular attraction. Threading is a simple elemental step of great importance to the formation of interlocked structures. It is well known that chemical templates can organize molecular cross-overs, through the use and location of their turns and anchors, but producing the first interlocked polymers and molecular cloths constitute daunting challenges that can depend on the yields of single steps of the sequential chemical reactions. Wasserman estimated the statistical probability for threading a linear molecule through a macrocycle to be less than 0.01, supported by experimental findings. Similarly, the classic study by Harrison and Harrison of rotaxane formation with the ring component bound to a Merrifield resin revealed that 70 successive applications of the statistical threading and blocking reactions resulted in only 6% of the rings being converted to rotaxane. In contrast, template threading is based on mutually attracting participants (to form a template complex). Many studies involving single threadings using various templates that give much higher yields—up to 92% in the best case with metathesis, have been reported.
Principle of Least Reagent
For interlocking turns, choosing and locating the terminal functional groups so that no additional linking atoms (or a minimum number) are required to complete the ring greatly facilitates the efficiency of catenane formation as shown in FIG. 4. The advantage probably derives in large part from the reduced competition between the formation of intramolecular and intermolecular linkages. Other advantages should stem from reclaiming the ability to use a large excess of a second reagent and the fact that no additional atoms are needed to form the final ring. This has been called the principle of least reagent which can be applied to obtain higher yields in catenane formation.
The Trefoil Knot
The trefoil knot is the simplest knot (outside of the unknot) that can be demonstrated. Sauvage has reported the synthesis of the first molecular example by linking two of his phenanthroline-based molecular turns together with a methylene group, producing a pair of linked turns. Complexation of such a ligand:conjugate with copper(I) gave a mixture of products, and, in the structure of greatest interest, two ligands combine with two copper(I) ions to form a double helical complex. The pair of didentate turns constituting a single ligand are twisted orthogonally (with respect to each other) at the linkage between the two copper ions. Creating two new links between each ligand in the double helical complex and the other by a pair of polyglycol chains producing a trefoil knot in 3% yield as shown in FIG. 5. Removal of the metal ion (demetalation) gives a molecule having the same linkages as a large macrocycle made up of two molecules of the double-turn and two molecules of the bridging unit. However, the new molecule is a knot and is topologically very different from the simple macrocycle (unknot)—the two topological isomers cannot be interconverted without breaking at least one chemical bond—the Trefoil Knot. The yield of the trefoil knot can be remarkably improved by replacing the methylene group connecting the pair of turns with an m-phenylene group. The extension of this helical approach to larger linear arrays of metal ions is possible. Sauvage pointed out that even numbers of cross-overs (i.e. tetrahedral copper(I) plus pairs of turns) always produces increasingly complex knots, while odd numbers of cross-overs lead to increasingly complex multiply interlocked [2]-catenanes as shown in FIG. 5.
2.3 RAFT Polymerization
RAFT polymerization is one of the more versatile and robust techniques in the spectrum of “living” or living radical polymerization methods, which includes atom transfer radical polymerization (ATRP), nitroxide mediated polymerization (NMP), and others. It is applicable to a broad range of monomers and polymerizations and can be conducted under conventional conditions, i.e. using existing recipes and equipment to which the RAFT iniferter is added. It has been shown that a minimum value of 10 on the transfer constant is required to obtain low polydispersity material in batch polymerizations. For RAFT polymerizations to obey the rules of living polymerizations, a few aspects in the reaction scheme are of importance: 1) A rapid exchange reaction, 2) Good homolytically leaving R group, capable of reinitiation, and 3) Constant number of chains during the polymerization. For the chain transfer agent (CTA) or iniferter, dithioesters are unsurpassed in activity by xanthates, trithiocarbonates and thiocarbamates. Aromatic dithioesters that contain a dithiobenzoate moiety are likewise common. For clarity and consistency in RAFT terminology, general reaction schemes make use of Z and R to indicate the activating group and the leaving group of the RAFT agent respectively as shown in FIG. 6. The structures of the R and Z groups are of critical importance to a successful RAFT polymerization. The R group of a RAFT agent is important in the pre-equilibrium stage of the polymerization. The R group should be a better leaving group than the propagating radical and must efficiently reinitiate monomer as an expelled radical. Steric factors, radical stability, and polar effects are significant in determining the leaving/reinitiating ability of an R group. Increased radical stability enables the R group to be a good leaving group; however, if the radical is too stabilized, it may not effectively add onto a monomer and reinitiate polymerization. The Z group of a RAFT agent is highly influential in determining its reactivity and consequently its effectiveness at mediating polymerization. The Z group should be chosen so that it will activate the C═S bond toward radical addition and then impart minimal stabilization of the adduct radical formed. If the stabilizing effect of the Z group is too high, fragmentation may not be favored and inhibition of the polymerization (in the initial step) or retardation (in the main process) might be observed. It is necessary to choose a Z group that is suitable for mediating the polymerization of a specific monomer.
Referring now to FIGS. 7a &b, a schematic representation of reversible addition fragmentation chain transfer using a dithioester Compound 1 is shown. FIG. 7a shows a reaction of the initial transfer agent with a propagating radical, forming a dormant species Compound 3 and releasing radical R. The expelled radical initiates polymerization and forms a propagating chain. FIG. 7b shows an equilibrium between active propagating chains and dormant chains with a dithioester moiety. Note that all reactions are equilibria, but that the k values refer to the downward direction of the reaction. Also note that these equilibria are not restricted to specific pairs of chains, but that any radical may react with any dormant species/RAFT agent.
Prior art shows that while a number of RAFT polymerization systems have been reported through the years under solution, bulk, and emulsion conditions, confined or even surface controlled RAFT polymerizations have specific and unique parameters. Thus, there is a need in the art for other systems and methods of making knotty polymers.